基于Poly(A)/二氧化硅纳米颗粒的pH可控释放抗肿瘤药物载体

利用异喹啉类生物碱小分子化合物与腺嘌呤(A碱基)在酸性条件结合力下降的特点,以具有良好生物相容性、DNA酶切保护性以及易于生物修饰的二氧化硅纳米颗粒为载体,发展了一种基于聚A链(Poly(A))/二氧化硅纳米颗粒(Poly(A)/SiNPs)的pH可控释放抗肿瘤药物体系.在该体系中,选择了甲氧檗因(coralyne)作为药物模式分子,通过共价修饰方法在二氧化硅纳米颗粒表面修饰Poly(A),获得Poly(A)/SiNPs颗粒,通过A碱基-甲氧檗因-A碱基结合方式构建了甲氧檗因载药体系.采用琼脂糖凝胶电泳、透射电子显微镜以及荧光光谱等方法对载药体系进行了表征,考察了载药体系的稳定性和在不同pH缓冲液中的释放情况,并采用激光共聚焦成像技术和MTT方法分别考察了该体系在Hela细胞内的定位以及杀伤效果.结果表明:Poly(A)被成功修饰在二氧化硅纳米颗粒上后能很好地与甲氧檗因结合,构建甲氧檗因载药体系,该体系在中性条件具有较好的稳定性,而在酸性条件下(pH6),由于甲氧檗因与A碱基的结合力减弱而被释放出来,实现pH的控制释放.细胞成像结果显示,该载药体系能被细胞内吞并聚集于溶酶体内,通过利用溶酶体的酸性环境释放药物,实现了对肿瘤细胞的杀伤.该体系较好地实现了甲氧檗因抗肿瘤药物的装载和释放,为发展这一类抗肿瘤药物的载体提供了新方法.

pH controlled release anticancer drug delivery based on poly(A)/SiO2 nanoparticles

In this work, a pH controlled release anticancer drug delivery based on poly(A)/silica nanoparticles has been developed by taking advantage of the weak interaction of isoquinoline alkaloid and adenine at acidic environment. In this design, the poly(A) was firstly modified on the surface of the silica nanoparticles through the EDC/NHS crosslinking. The coralyne was selected as a model drug. Through the adenine-coralyne-adenine binding, the coralyne then can be loaded onto the poly(A)/silica nanoparticles to form coralyne-poly(A)/silica nanoparticles complex. The properties of poly(A)/silica nanoparticles and coralyne-poly(A)/silica nanoparticles complex were characterized by agarose gel electrophoresis, transmission electron microscopy (TEM) and fluorescence spectroscopy. The stability of the coralyne-poly(A)/silica nanoparticles complex and the effect of drug release at different pH buffer were investigated. In addition, the intracellular behavior of coralyne-poly(A)/silica nanoparticles in Hela cells was further studied by using laser confocal scanning microscopy and MTT assay. The results showed that the coralyne-poly(A)/silica nanoparticles exhibited a good stability at neutral pH buffer. At acidic environment (pH<6), the coralyne was released easily from the nanoparticles complex because the hydrogen bonds interaction between coralyne and adenine was getting weak. Therefore, the release of coralyne could be controlled by changing pH. The further cells experiments demonstrated that the coralyne-poly(A)/silica nanoparticles could be endocysised by the Hela cells and demonstrated highly efficient operation at lysosomal pH, while the poly(A)/silica nanoparticles was relative biocompatible and suitable to use as drug carriers. This research provided a new way for the isoquinoline alkaloid drug delivery system.